1. Field of the Invention
The present invention relates to a process for the enantiomeric enrichment of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo-[4.3.0]nonane with the aid of continuous countercurrent chromatography, in particular, SMB chromatography (SMB=simulated moving bed). In a further aspect, the invention relates to a process for the preparation of (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane using the aforementioned process, which furthermore includes a racemization step.
2. Brief Description of the Prior Art
The enantiomers of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane (DOPP) are valuable intermediates for the preparation of quinolone- and naphthyridone-carboxylic acid derivatives which, inter alia, have gained great industrial importance as an active constituent of antibacterial agents and food additives (EP-A 550 903).
(1S,6R)-8-Benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane of the formula (Ia)
is, for example, a valuable intermediate for the preparation of (S,S)-2,8-diazabicyclo[4.3.0]nonane (IIa),
into which it can be converted by reduction of the carbonyl groups and debenzylation in a manner known per se (EP-A 350 733). (S,S)-2,8-Diazabicyclo[4.3.0]nonane is, for its part, used for the preparation of the antibiotic moxifloxacin (INN, 1-cyclo-propyl-7-([S,S]-2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolonecarboxylic acid, (III)) (EP-A 350 733): (III)
The enantiomer (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane (Ib)
is in turn a valuable intermediate for the preparation of (R,R)-2,8-diazabicyclo[4.3.0]nonane (IIb),
which can likewise be used for the preparation of very active antibacterial agents (e.g. Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 1996, Abstr. No. F-001).
Processes for the enantiomeric enrichment of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane are known in principle.
Thus, for example, EP-A 550 903 discloses a process for the resolution of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane using tartaric acid (Example A, Method IV and Example B, Method II a)). The processes described there require, for the preparation of the (1S,6R)-enantiomer, repeated recrystallization of the diastereomeric D-(−)-tartaric acid salts or reaction with L-(+)-tartaric acid and subsequent reaction of the released mother liquor with D-(−)-tartaric acid and recrystallization. The enantiomeric excesses obtained are, at 93.8% ee for the (1R,6S) enantiomer and 96.6% ee for the (1S,6R) enantiomer, inadequate with respect to the large number of operations and the large amount of chiral auxiliary reagants and thus only of limited suitability for industrial use.
EP-A 1 192 153 discloses a process for the resolution of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, which, inter alia, employs (−)-2,3:4,6-di-O-iso-propylidene-2-keto-L-gulonic acid and camphorsulphonic acid as chiral auxiliary reagents. However, here too, the amount of chiral auxiliary reagent needed and the large number of working steps restricts industrial use.
There was therefore the need for an efficient process for the enantiomeric enrichment of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, in which the separated enantiomers can be prepared on an industrial scale and in high absolute and optical purity.